Project Summary The goal of this program is to discover the next generation of drugs for bipolar depression and maintenance (BPD), a brain disorder that affects ~6 million adult Americans. Existing drug classes are relatively ineffective and very few new modes-of-action (MOAs) have been developed in the past 25+ years. This is due, in part, to the lack of predictive preclinical BPD disease models and the biopharma industry focus on drugging single molecular targets. Our scientific premise is that first-in-class drugs will be discovered by testing novel, custom-designed privileged chemotypes using a proven behavioral profiling method and ex vivo imaging of the forebrain circuits implicated in BPD. We successfully employed this target- agnostic strategy to discover and optimize novel clinical drugs for psychiatric illness: one is currently in Phase 2 trials for schizophrenia and another is in Phase 1 clinical trials. We founded Blue Oak Pharmaceuticals in order to further advance this research paradigm and discover the next generation of drugs for BPD. Our research plan: Aim 1: Develop a ?behavioral map? for BPD reference drugs and screen the Blue Oak privileged chemotype library. We will utilize the SmartCube technology to generate deep behavioral profiles of the existing BPD drugs/combinations. Our library of novel candidate privileged chemotypes, designed to be CNS active and drug-like, will also be screened to identify profiles similar to the reference BPD drugs. Aim 2: Map brain circuit activity to prioritize lead chemotypes. A lead chemotype with a novel MOA will be selected that is inactive at known molecular targets for existing BPD drugs but modulates mesolimbic/mesocortical dopamine, glutamate and GABAergic pathways. Aim 3: Optimize clinical candidate(s). Clinical candidate(s) will be achieved by maximizing in vivo efficacy, optimizing ADME properties and establishing intellectual property. An important translational medicine goal is to identify compounds that enhance EEG gamma power as a biomarker for use in Phase 1 clinical studies. To execute this program effectively, we will utilize the ?research network? model that we have developed over the past 10 years. This world-class team includes Blue Oak ?drug hunters? who are experts in systems neurobiology, medicinal chemistry and informatics. We will enable our research strategy with established partners that have cutting edge technologies in behavioral profiling, synthetic chemistry and brain imaging. Our clinical and business advisors have proven track records in drug development and commercialization. This program will generate several paths that transform therapeutics for brain disorders: BPD clinical candidate(s) with translational medicine biomarkers and improved safety, efficacy profiles. Pharmacological tools for identifying cellular pathways and novel target(s) involved in BPD. Privileged chemotypes and a behavioral profiling database that provides excellent starting points for additional drug discovery programs for other brain disorders.